Accurate and highly interpretable prediction of gene expression from histone modifications.

BACKGROUND: Histone Mark Modifications (HMs) are crucial actors in gene regulation, as they actively remodel chromatin to modulate transcriptional activity: aberrant combinatorial patterns of HMs have been connected with several diseases, including cancer. HMs are, however, reversible modifications: understanding their role in disease would allow the design of 'epigenetic drugs' for specific, non-invasive treatments. Standard statistical techniques were not entirely successful in extracting representative features from raw HM signals over gene locations. On the other hand, deep learning approaches allow for effective automatic feature extraction, but at the expense of model interpretation. RESULTS: Here, we propose ShallowChrome, a novel computational pipeline to model transcriptional regulation via HMs in both an accurate and interpretable way. We attain state-of-the-art results on the binary classification of gene transcriptional states over 56 cell-types from the REMC database, largely outperforming recent deep learning approaches. We interpret our models by extracting insightful gene-specific regulative patterns, and we analyse them for the specific case of the PAX5 gene over three differentiated blood cell lines. Finally, we compare the patterns we obtained with the characteristic emission patterns of ChromHMM, and show that ShallowChrome is able to coherently rank groups of chromatin states w.r.t. their transcriptional activity. CONCLUSIONS: In this work we demonstrate that it is possible to model HM-modulated gene expression regulation in a highly accurate, yet interpretable way. Our feature extraction algorithm leverages on data downstream the identification of enriched regions to retrieve gene-wise, statistically significant and dynamically located features for each HM. These features are highly predictive of gene transcriptional state, and allow for accurate modeling by computationally efficient logistic regression models. These models allow a direct inspection and a rigorous interpretation, helping to formulate quantifiable hypotheses.

SMfinder: Small Molecules Finder for Metabolomics and Lipidomics Analysis.

Metabolomics and lipidomics studies are becoming increasingly popular but available tools for automated data analysis are still limited. The major issue in untargeted metabolomics is linked to the lack of efficient ranking methods allowing accurate identification of metabolites. Herein, we provide a user-friendly open-source software, named SMfinder, for the robust identification and quantification of small molecules. The software introduces an MS2 false discovery rate approach, which is based on single spectral permutation and increases identification accuracy. SMfinder can be efficiently applied to shotgun and targeted analysis in metabolomics and lipidomics without requiring extensive in-house acquisition of standards as it provides accurate identification by using available MS2 libraries in instrument independent manner. The software, downloadable at www.ifom.eu/SMfinder, is suitable for untargeted, targeted, and flux analysis.

A comparison of femorocrural bypasses performed with modified heparin-bonded expanded polytetrafluorethylene grafts and those with great saphenous vein grafts to treat critical limb ischemia.

BACKGROUND: The purpose of this study was to evaluate our results involving femorocrural bypasses by comparing heparin-bonded expanded polytetrafluoroethylene (HePTFE) graft (Propaten) modified with handmade distal compliant HePTFE cuffs (mHePTFE graft) to great saphenous vein (GSV) graft. METHODS: A retrospective study involving 74 femorocrural bypasses performed from January 2010 to May 2013 at a single institution was carried out. The indication for revascularization was critical limb ischemia (Rutherford stages 4-6. Forty-one femorocrural bypasses were created in 37 patients with unavailable GSVs using modified ringed HePTFE grafts with a handmade distal radial stretch HePTFE cuff to reduce the mismatch compliance between the graft and the artery wall. Thirty-three femorocrural bypasses were created using a reversed GSV graft. The results were analyzed in terms of primary graft patency, limb salvage, and patient survival using univariate (Kaplan-Meier curves and log-rank test) and multivariate (Cox regression) analyses. RESULTS: The 2 groups were statistically comparable for main risk factors, Rutherford stage, and target artery for distal anastomoses. The run-off anatomy did not significantly differ between the prosthetic and the vein bypass group. The cumulative 30-day operative mortality rate was 2.9%. At 1, 2, and 3 years, the 2 groups were equivalent in primary graft patency (the mHePTFE group: 84%, 80%, and 70%, respectively; the GSV group: 84%,71%, and 71%, respectively; P = 0.93) and were also equivalent in terms of limb salvage (the mHePTFE group: 87%, 87%, and 76%, respectively; the GSV group: 84%, 75%, and 75%, respectively; P = 0.78) and patient survival (the mHePTFE group: 87%, 75%, and 75%, respectively; the GSV group: 87%, 73%, and 65%, respectively; P = 0.86). At Cox regression analysis, only postoperative treatment with warfarin therapy compared with double antiplatelet therapy was independently associated with poorer primary patency (P = 0.003; 95% confidence interval, 1.80-18.00; hazard ratio, 5.7). CONCLUSIONS: In this retrospective study regarding femorocrural bypasses, the mHePTFE grafts had 1-, 2-, and 3-year primary patency and limb salvage results which were not significantly different from those in the GSV grafts. Additional randomized data and larger studies are needed to confirm these results.

Immediate loading of single implants inserted flapless with medium or high insertion torque: a 6-month follow-up of a split-mouth randomised controlled trial.

PURPOSE: To compare the outcome of immediately loaded single implants inserted with medium (from 25 to 35 Ncm) or high insertion torques (>80 Ncm). MATERIALS AND METHODS: Fifty patients received two single non-adjacent implants, each randomly inserted flapless with a torque between 25 to 35 Ncm or >80 Ncm according to a split-mouth design. Non-occluding temporary crowns were immediately placed on provisional abutments and definitive crowns were delivered after 6 weeks. Patients were followed for 6 months after initial loading. Outcome measures were crown/implant failures, complications, peri-implant marginal bone level changes, postoperative pain and presence of peri-implant apical radiolucency. RESULTS: No drop-out occurred. Seven implants inserted with a torque between 25 to 35 Ncm failed versus none of the implants inserted with a torque >35 Ncm. With the exception of crown/implant failures (exact McNemar significance P = 0.0156, difference in proportions: -0.12; 95% CI -0.21 to -0.02) there were no statistically significant differences between groups for the other outcome measures. CONCLUSIONS: It is preferable to insert single implants with a high insertion torque (>80 Ncm), to minimise early implant failures, when loading them immediately.

Flapless versus open flap implant surgery in partially edentulous patients subjected to immediate loading: 1-year results from a split-mouth randomised controlled trial.

PURPOSE: To evaluate the efficacy of flapless versus open flap implant placement in partially edentulous patients. MATERIALS AND METHODS: Forty patients with two separate edentulous areas characterised by residual bone at least 5 mm thick and 10 mm in height had these sites randomised following a split-mouth design to receive at least one implant to each side after flap elevation or not. Implants were first placed in one site, and after 2 weeks in the other site freehand. Implants inserted with a torque >48 Ncm were immediately loaded with full occluding acrylic temporary restorations. Definitive single cemented crowns or screw-retained metal ceramic fixed dental prostheses were delivered after 2 months. Outcome measures were prosthesis and implant failures, complications, postoperative swelling and pain, consumption of analgesics, patient preference, surgical time, marginal bone level changes, and implant stability quotient (ISQ) values. RESULTS: Seventy-six implants were placed flapless and 67 after flap elevation. In the flapless group, four flaps had to be raised to control the direction of the bur, whereas one haemorrhage and one fracture of the buccal bone occurred in two patients of the flap elevation group. Four implants did not reach the planned stability (three belonging to the flapless group) and they were all immediately replaced by larger diameter ones. After 1 year, no drop-outs occurred. Two definitive bridges could not be placed when planned (one in each group) and two crowns had to be remade (one in each group). Two implants failed in each group, all in different patients. There were no statistically significant differences for prosthetic and implant failures, complications, ISQ values and marginal bone levels between groups. However, flapless implant placement required significantly less operation time (17 minutes less, saving almost two-thirds of the time for implant placement), induced less postoperative pain, swelling, analgesic consumption and was preferred by patients. Mean ISQ values of both groups significantly decreased over time. CONCLUSIONS: Implants can be successfully placed flapless and loaded immediately, reducing treatment time and patient discomfort.

Immediate functional loading of implants placed with flapless surgery versus conventional implants in partially edentulous patients: a 3-year randomized controlled clinical trial.

PURPOSE: To compare the efficacy of immediate functionally loaded implants placed with a flapless procedure (test group) versus implants placed after flap elevation and conventional load-free healing (control group) in partially edentulous patients. MATERIALS AND METHODS: Forty patients were randomized: 20 to the flapless immediately loaded group and 20 to the conventional group. To be immediately loaded, implants had to be inserted with a minimum torque > 45 Ncm. Implants in the immediately loaded group were provided with full acrylic resin temporary restorations the same day. Implants in the conventional group were submerged (anterior region) or left unsubmerged (posterior region) and were left load-free for 3 months (mandibles) or 4 months (maxillae). Provisional restorations were replaced with definitive single metal-ceramic crowns 1 month postloading. Outcome measures were prosthesis and implant failures, biological and prosthetic complications, postoperative edema, pain, and use of analgesics. Independent sample chi2 tests, Mann-Whitney tests, t tests, and paired t tests were used with a significance level of .05. RESULTS: Fifty-two implants were placed in the flapless group and 56 in the conventionally loaded group. In the flapless group, 1 flap had to be raised to control the direction of the bur and 1 implant did not reach the planned primary stability and was treated as belonging to the conventional group. After 3 years no dropouts or failures occurred. There was no statistically significant difference for complications; however, patients in the conventional group had significantly more postoperative edema and pain and consumed more analgesics than those in the flapless group. Osstell values were significantly higher at baseline in the flapless group (P = .033). When comparing baseline data with years 1, 2, and 3 within each group, mean Osstell values of the flapless group did not increase, whereas there were statistically significant increases in the Periotest values. CONCLUSIONS: Implants can be successfully placed flapless and loaded immediately without compromising success rates; the procedure decreases treatment time and patient discomfort.

Immediate versus early loading of two implants placed with a flapless technique supporting mandibular bar-retained overdentures: a single-blinded, randomised controlled clinical trial.

PURPOSE: To evaluate the efficacy of immediate loading versus early loading at 6 weeks of bar-retained mandibular overdentures supported by two implants placed with a flapless technique. MATERIALS AND METHODS: Sixty patients were randomised: 30 to the immediately loaded group and 30 to the early loaded group. To be immediately loaded, implants had to be inserted with a minimum torque > 48 Ncm. Outcome measures were prosthesis and implant failures, biological and biomechanical complications, patient satisfaction, and Implant Stability Quotient (ISQ) assessed with a resonance frequency analysis instrument. RESULTS: Sixty implants were placed in each group. Flaps had to be raised in nine patients to check drill direction or to better visualise the area after multiple teeth extraction. Two implants in two patients did not reach the planned insertion torque and were immediately replaced by larger diameters ones. After 1 year no drop out occurred and two early loaded implants failed in two patients. There were no statistically significant differences between groups for prosthesis failures, implant losses, complications, and mean ISQ values; however, patients in the immediately loaded group were significantly more satisfied than those loaded early. When comparing mean ISQ values taken 6 weeks after placement with 1-year data within each group, values decreased significantly. CONCLUSIONS: Mandibular overdentures can be successfully loaded the same day of implant placement with a minimally invasive surgery, increasing patient satisfaction while decreasing treatment time and patient discomfort. No apparent advantages were seen when loading the overdentures at 6 weeks.

Clustering by soft-constraint affinity propagation: applications to gene-expression data.

MOTIVATION: Similarity-measure-based clustering is a crucial problem appearing throughout scientific data analysis. Recently, a powerful new algorithm called Affinity Propagation (AP) based on message-passing techniques was proposed by Frey and Dueck (2007a). In AP, each cluster is identified by a common exemplar all other data points of the same cluster refer to, and exemplars have to refer to themselves. Albeit its proved power, AP in its present form suffers from a number of drawbacks. The hard constraint of having exactly one exemplar per cluster restricts AP to classes of regularly shaped clusters, and leads to suboptimal performance, e.g. in analyzing gene expression data. RESULTS: This limitation can be overcome by relaxing the AP hard constraints. A new parameter controls the importance of the constraints compared to the aim of maximizing the overall similarity, and allows to interpolate between the simple case where each data point selects its closest neighbor as an exemplar and the original AP. The resulting soft-constraint affinity propagation (SCAP) becomes more informative, accurate and leads to more stable clustering. Even though a new a priori free parameter is introduced, the overall dependence of the algorithm on external tuning is reduced, as robustness is increased and an optimal strategy for parameter selection emerges more naturally. SCAP is tested on biological benchmark data, including in particular microarray data related to various cancer types. We show that the algorithm efficiently unveils the hierarchical cluster structure present in the data sets. Further on, it allows to extract sparse gene expression signatures for each cluster.

Immediate functional loading of implants placed with flapless surgery in the edentulous maxilla: 1-year follow-up of a single cohort study.

PURPOSE: To evaluate success rates and complications of implants placed with a flapless technique and immediately loaded in fully edentulous maxillae. MATERIALS AND METHODS: Implants were placed in fully edentulous maxillae with a minimum insertion torque of 45 Ncm in underprepared sites to allow maximum stability at insertion using a flapless technique. Implants were immediately loaded. Outcome measures were prosthesis and implant success, biologic and prosthetic complications, pain, and edema evaluation. Stability of individual implants was assessed both manually and with Osstell at baseline and after 12 months of loading. A single sample t test was used with a significance level of .05. RESULTS: Thirty-three consecutively treated edentulous patients received 202 implants in the maxilla. In 10 patients, 53 implants were immediately inserted in fresh extraction sockets. At implant insertion, a flap had to be elevated to control the direction of the drill in 5 patients. Three implants in 2 patients did not reach sufficient stability and were left to heal for 45 to 90 days. All restorations (21 fixed prostheses and 12 overdentures) were delivered the same day of the surgery. Twenty-six patients experienced no or slight postoperative pain; 7 experienced moderate to severe pain. No or slight edema was recorded for 19 patients and moderate to severe edema for 14 patients. Two implants failed in 2 patients but were successfully replaced the same day they were removed. No major complications occurred. Five patients experienced biologic complications, eg, peri-implantitis; 10 experienced prosthetic complications. No prosthesis failed; however, 1 patient was unsatisfied with his overdenture and requested a fixed alternative. There was a highly significant difference (P < .001) between the stability at implant insertion and after 12 months. CONCLUSION: Implants placed in the edentulous maxilla with a flapless procedure can be successfully loaded the same day of surgery.